Multiple myeloma (MM) is the second most commonly diagnosed hematologic cancer and remains incurable with current therapies. Biomedical imaging techniques such as 18F-fluorodeoxyglucose (FDG)/Positron Emission Tomography (PET), skeletal survey, bone scintigraphy and Magnetic Resonance Imaging (MRI) are routinely used for staging and post-treatment follow up in MM patients. More importantly, imaging of the skeleton with the aim of detecting lytic bone lesions is needed to discriminate MM from its precursor states such as smoldering MM (sMM) and monoclonal gammopathy of undetermined significance (MGUS). Many effective chemotherapy agents are available for MM patients, but the optimal use of these agents is not clear and a vast majority of patients relapse and die from their disease. All currently available imaging modalities take months to demonstrate tumor responses and therefore are of limited utility for clinical trials requiring rapi evaluation of treatment responses. FDG is a marker of cell metabolism that has limited sensitivity (61%) for intramedullary lesions in MM. Receptor-mediated interactions between myeloma cells and BM milieu support tumor survival. Very late antigen-4 (VLA-4; also called alpha4beta1 integrin) is one of the critical mediators of myeloma cell adhesion to the BM stroma. VLA-4 promotes myeloma cell trafficking, proliferation, differentiation and drug resistance. Clinically, high-levels of VLA-4 predict a poor prognosis in MM patients. In this proposal, we will develop a high-affinity and high-specific activity, copper-64 labeled VLA-4 targeted PET radiopharmaceutical (64Cu-LLP2A) to assess disease progression and response to treatment in pre-clinical models of mouse and human MM by quantitatively imaging VLA-4. The goal of aim 1 is twofold: a) to optimize the first-generation agent to enhance solubility and improve pharmacokinetics; and b) to synthesize optical and scrambled analogs for in vitro and in vivo binding specificity evaluations. Aim 2a will develop an imaging method using 64Cu- LLP2A/PET that can detect myeloma cells and myeloma induced bone lesions when they are significantly smaller than those currently detected with existing diagnostic tests and imaging methods. Finally, Aim 2b will focus on the monitoring of therapeutic responses using bortezomib (a proteasome inhibitor) and zoledronic acid (a bisphosphonate) at early and late time points. These aims will help in the accurate assessment of early stage disease and treatment response by sensitive and specific VLA-4 targeted PET imaging.